Analysis of cardiac safety of pertuzumab combined with trastuzumab and standard chemotherapy in patients with HER2-positive breast cancer revealed no new safety signals
Cardiac safety and general safety of pertuzumab in combination with trastuzumab and two different anthracycline-containing regimens were as expected and were consistent with the known safety profiles of pertuzumab, trastuzumab and anthracycline-based chemotherapy. This could be concluded from a primary analysis of the BERENICE study which was presented at SABCS 2016. Although no long-term clinical outcomes from BERENICE were available at the time of the primary analysis, pathologic complete response (pCR) rates were high and consistent with findings from previous studies.
The addition of neoadjuvant pertuzumab to the combination of trastuzumab plus anthracycline-based chemotherapy significantly increases pCR rates compared to trastuzumab plus chemotherapy alone. However, the risk of cardiac toxicity can be increased by combining anti-HER2 therapy with chemotherapy, especially following anthracyclines. Therefore, cardiac safety is an important consideration when using these regimens. Data on neoadjuvant pertuzumab and trastuzumab within a fluorouracil, epirubicin, and cyclophosphamide plus taxane based regimen are limited or lacking.
The multicentre, non-randomized, open-label, phase II BERENICE study was designed to evaluate the cardiac safety and efficacy of pertuzumab in combination with trastuzumab and anthracycline-based chemotherapy as neoadjuvant treatment in patients with locally advanced, inflammatory, or early-stage, unilateral, invasive HER2-positive breast cancer. The primary endpoints were the incidence of New York Heart Association (NYHA) Class III and IV heart failure during neoadjuvant treatment, and the incidence of all left ventricular ejection fraction (LVEF) declines (of ≥10 percentage points from baseline and to a value of <50%) by echocardiography or multiple-gated acquisition (MUGA) scan during neoadjuvant treatment. Secondary endpoint included an evaluation of safety (adverse events rates) and pCR rates.
Each investigator chose a treatment regimen (A or B) for all their patients to follow. Patients in cohort A (N=199) received doxorubicin (60mg/m2 IV) and cyclophosphamide (600mg/m2 IV), followed by paclitaxel (80mg/m2 IV), pertuzumab (420mg IV) and trastuzumab (6mg IV) for 4 cycles. In cohort B (N=201), patients received 5-fluorouracil (500mg/m2 IV), epirubicin (100mg/m2 IV), and cyclophosphamide (600mg/m2 IV), followed by docetaxel (100mg/m2 IV), pertuzumab (420mg IV) and trastuzumab (6mg IV) for 4 cycles. Patients in both cohorts subsequently underwent surgical treatment and then resumed pertuzumab and trastuzumab treatment.
At data cutoff for the primary analysis the median follow-up was 14.5 months in cohort A and 15.1 months in cohort B. Patients in both cohorts were treated for a median of 12.0 weeks at that time. In total, 3 patients experienced a total of 4 NYHA Class III/IV heart failure events, all in cohort A and all during cycles 5-8 (taxane plus anti-HER2 therapy). At least 1 LVEF decline was observed in 13 patients (6.5%) in cohort A, and 4 patients (2.0%) in cohort B. Adverse events and serious adverse events were well balanced between cohorts. The most common adverse events were nausea (70.9% in cohort A versus 69.2% in cohort B), diarrhoea (66.8% versus 69.2%), and alopecia (62.3% versus 58.6%). Seven percent of patients in cohort A and 17.2% of patients in cohort B experienced grade ≥3 febrile neutropenia, 12.1% and 8.6% , respectively, experienced grade ≥3 neutropenia, and 3.0% and 10.1%, respectively, experienced grade ≥3 diarrhoea. The pCR rates were similar between cohorts: 61.8% in cohort A and 60.7% in cohort B.
Overall, the BERENICE study showed that neoadjuvant treatment with pertuzumab plus trastuzumab within commonly used chemotherapy regimens resulted in a consistent cardiac and general safety profile compared to previous studies, with no new safety issues identified. When considering the high pCR rates observed in both cohorts, these data are supportive of the positive benefit-risk profile for pertuzumab in the neoadjuvant setting for both treatment regimens.
Swain SM, Ewer MS, Viale G, et al. Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer. San Antonio Breast Cancer Symposium 2016, abstract P4-21-41.